Method of treating chronic kidney disease

ABSTRACT

The present invention discloses pharmaceutical-grade ferric organic compounds having enhanced dissolution rate. These ferric organic compounds, including but are not limited to ferric citrate, are useful for treating chronic kidney disease.

This application is a continuation of U.S. patent application Ser. No.17/119,554, filed Dec. 11, 2020, which is a continuation of U.S. patentapplication Ser. No. 15/814,767, filed Nov. 16, 2017 and issued as U.S.Pat. No. 10,898,459 on Jan. 26, 2021, which is a continuation of U.S.patent application Ser. No. 12/162,543, filed Oct. 29, 2008, nowabandoned, which is a National Stage Application filed under 35 U.S.C. §371, of International Patent Application No. PCT/US2007/002151, filedJan. 26, 2007, which claims priority to and the benefit of InternationalPatent Application No. PCT/US2006/032385 filed Aug. 18, 2006 and U.S.Provisional Patent Application No. 60/763,253 filed Jan. 30, 2006, eachof which is incorporated by reference herein in its entirety.

Throughout this application, various publications are referenced.Disclosures of these publications in their entireties are herebyincorporated by reference into this application to more fully describethe state of the art to which this invention pertains.

FIELD OF THE INVENTION

This invention relates to the uses of pharmaceutical-grade ferricorganic compounds to treat chronic kidney disease.

BACKGROUND OF THE INVENTION

Chronic kidney disease is a gradual and progressive loss of the abilityof the kidneys to excrete wastes, concentrate urine, and conserveelectrolytes. Unlike acute kidney failure with its abrupt but reversibleof kidney function, the kidney functions in chronic kidney diseaseprogress and deteriorate irreversibly towards end stage renal disease(ESRD). Patients suffering from ESRD cannot survive without dialysis orkidney transplantation.

The U.S. National Kidney Foundation defines chronic kidney diseaseaccording to the presence or absence of kidney damage and the level ofkidney function, regardless of the type (clinical diagnosis) of kidneydisease. The primary measure of kidney function is glomerular filtrationrate (GFR), which is often estimated as creatinine clearance from serumand urine creatinine concentrations. Chronic kidney disease or failureis defined as having glomerular filtration rate less than 60 ml/min forthree months or more. The U.S. National Kidney Foundation has suggesteda five-stage classification of renal dysfunction based on glomerularfiltration rate:

Stages of renal dysfunction (adapted from National KidneyFoundation-K/DOQI) Creatinine Clearance Stage Description (~GFR:ml/min/1.73 m²) Metabolic consequences 1 Normal or increased GFR- >90 —People at increased risk or with early renal damage 2 Early renalinsufficiency 60-89 Concentration of parathyroid hormone starts to rise(GFR ~60-80) 3 Moderate renal failure 30-59 Decrease in calciumabsorption (GFR < 50) (chronic renal failure) Lipoprotein activity fallsMalnutrition Onset of left ventricular hypertrophy Onset of anaemia 4Severe renal failure 15-29 Triglyceride concentrations start to riseHyperphosphatemia Metabolic acidosis Tendency to hyperkalemia 5 Endstage renal disease <15 Azotaemia develops (Uremia)

According to the U.S. National Kidney Foundation, there are in excess of20 million U.S. citizens, representing approximately 11 percent of thepopulation, suffering from chronic kidney disease, with a further 20million at increased risk. The high prevalence rate of chronic kidneydisease poses a significant burden on the healthcare system. One of themost apparent economic costs associated with chronic kidney disease isthe development of end stage renal disease which, in the U.S. alone,costs approximately U.S. $23 billion in 2001 and is estimated toincrease to U.S. $35 billion a year in 2010. For patients in earlierstage of chronic kidney disease, a review article has reported overallincreased costs of U.S. $14,000 to U.S. $22,000 per patient per yearcompared to age-matched general population.

Pathogenesis of progressive renal injury is complex and multi-factorial,and the current understanding is mainly based on experimental animalmodels. Chronic kidney disease often progresses by “common pathway”mechanisms, irrespective of the initiating insult. Early studies ofrenal dysfunction focused on functional and structural glomerularchanges. Recently, there has been increased interest intubulointerstitial changes as a major determinant of progressive renalinjury, and one of the key factors is the generation of calciumphosphate precipitation in urinary space and interstitium. Progressionof chronic kidney disease occurs from chronic tubulointerstitialinflammation caused by increases in single nephron filtered load ofphosphate, absolute tubular re-absorption of phosphate, calciumphosphate product in the tubular lumen and by precipitation of calciumphosphate in the tubules and interstitium, which is facilitated byreduced concentration of citrate in the tubular fluid(precipitation-calcification hypothesis).

The precipitation-calcification hypothesis is supported in experimentalanimals showing that a high phosphate diet aggravates chronic kidneydisease, whereas a low-phosphate diet, administration of phosphatebinders, and 3-phosphocitrate (an inhibitor of calcium phosphateprecipitation) slows progression of chronic kidney disease. Based onthese results, lowering serum phosphate and calcium phosphate productlevels as well as increasing serum citrate and 3-phosphocitrate levelsmay decrease the damage of the nephron and subsequently delay theprogress of chronic kidney disease. It has been reported that by slowingdown the progression rate of chronic kidney disease by 30% (as definedas decreasing the rate of decline in glomerular filtration rate by 30%)between 2000 and 2010, the estimated potential cumulative directhealthcare savings would be US $60.61 billion.

Hyperparathyroidism is one of the earliest manifestations of impairedrenal function, and minor changes in bone have been found in patientswith a glomerular filtration rate of 60 ml/min (chronic kidney diseasestage 2 to 3). With the worsening of kidney condition and phosphorusaccumulation, parathyroid will continuously increase the release ofparathyroid hormone (PTH) and lead to the development ofhyperparathyroidism. High PTH will increase calcium release from bone toserum. The result is abnormal serum concentrations of calcium andphosphorus and lead to bone disease and extraskeletal calcification.Precipitation of calcium phosphate in renal tissue begins early. Thismay influence the rate of progression of renal disease, and is closelyrelated to hyperphosphatemia and calcium phosphate (CaxP) product.

Acid-base balance is normally maintained by renal excretion of the dailyacid load. As renal function declines, the acid-base balance ismaintained by various compensatory mechanisms, of which an increase inthe synthesis of ammonia by proximal tubule is the most important. Adefective trapping of ammonia in the medulla poses further demands onproximal tubules to increase synthesis of ammonia and results in anenhanced concentration of ammonia in renal cortex. High concentration offree-base ammonia in renal cortex can result in complement activationand interstitial inflammation which has been reported to be one of themajor determinant of progressive renal injury. Renal acidosis result inbone demineralization, hyperparathyroidism, increase protein catabolism,insulin resistance and stunted growth. Recent observations suggest thatacidosis triggers inflammation and accelerates progression of chronickidney disease.

Chronic metabolic acidosis can result in protein metabolism and thusincreased excretion of urate and formation of kidney stones. If nottreated, kidney stone could cause urine obstruction, urinary tractinfection and may result in development of chronic kidney disease.

Once the degeneration process of kidney begins, there is no cure forchronic renal failure to date. As a preventive measure at the earlystage, it has been suggested to identify and treat the underlyingcondition as urinary track infection, obstruction, kidney stone or stoptaking drugs with nephrotoxic effects (i.e., NSAIDs) before chronickidney disease can be developed. It is also suggested to change dietplans (i.e., low protein diet) in the early stage. In addition,hypertension and diabetes have been identified as the most common riskfactors of the disease. The benefits of using antihypertensive therapyon the progression of chronic kidney disease have been extensivelyexamined. Uses of angiotension converting enzyme inhibitors (ACEIs) andangiotension receptor blockers (ARBs) have shown to be beneficial amongpatients with or without diabetes as well as those with or withoutproteinuria.

However, in reality many physicians fail to use these drug classes inpatients with renal insufficiency because these two classes of drug maypotentially increase the level of either serum creatinine (an indicationof renal deterioration) or potassium (most common life-threateningemergency in patient with end stage renal disease). It has beensuggested that these drugs not to be used in patients with advancedrenal failure, bilateral renal artery stenosis, and renal arterystenosis in a solitary kidney. Therefore, these drugs appear not to becommonly used on patients who already developed renal disease, and thesedrugs are not expected to delay the progression of chronic kidneydisease.

In additional to treating or preventing progression of chronic kidneydisease, other medications such as iron and erythropoietin supplementsare needed to control anemia in chronic kidney disease patients. NaHCO₃is used to ameliorate one of the uremic syndromes such as metabolicacidosis which leads to osteopenia and urinary calcium excretion.

Ferric iron containing compounds are useful in the treatment of a numberof disorders, including, but not limited to, hyperphosphatemia andmetabolic acidosis. See Hsu et al., New Phosphate Binding Agents: FerricCompounds, J Am Soc Nephrol. 10:1274-1280 (1999). Previous studies andinventions have reported the use of ferric compounds in binding dietaryphosphates, and such ferric compounds are potentially useful for thetreatment of hyperphosphatemia in renal failure patients (U.S. Pat. Nos.5,753,706; 6,903,235; CN 1315174; Yang et al., Nephrol. Dial. Transplant17:265-270 (2002)). Elevated amounts of phosphate in the blood can beremoved by administering compounds such as ferric citrate. Once insolution, the ferric iron binds phosphate, and the ferric phosphatecompounds precipitate in the gastrointestinal tract, resulting ineffective removal of dietary phosphate from the body. It is alsobelieved that the absorbed citrate from ferric citrate is converted tobicarbonate which corrects metabolic acidosis, a condition common inrenal failure patients.

U.S. Pat. No. 5,753,706 discloses the use of ferric containingcompounds, including ferric citrate and ferric acetate in thecrystalline form, in an orally effective 1 gram dosage form to bind tosoluble dietary phosphate, thus causing precipitation of phosphate asferric or ferrous phosphates in the gastrointestinal tract andpreventing oral absorption of soluble phosphates from dietary sources.Since binding of ferric ions to soluble phosphate in thegastrointestinal tract would require dissolution of the orallyadministered ferric citrate, and since the rate of dissolution ofcrystalline ferric citrate is slow (over 10-12 hours at 37° C.), oraladministration of a substantially large dose of 1 g of ferric citrate isrequired. A related Chinese patent application (CN 1315174) alsodiscloses a similar use of ferric citrate and related compounds in anoral solution dosage form for the treatment of hyperphosphatemia inrenal failure patients.

Fe (III) is a Lewis acid and is chemically less soluble in the stomachat pH below 5 than at intestinal pH normally above 7. The stomach is,however, believed to be an important site of action for the dissolutionof Fe (III) compounds. It is believed that the stomach is an importantsite of action for Fe (III) to mediate its action in binding to dietaryphosphates, preventing phosphate from reaching the intestine and thusreducing absorption of phosphates from the intestine.

Int'l App. No. PCT/US2004/004646, filed Feb. 18, 2004, published underInt'l Publication No. WO2004/074444 on Sep. 2, 2004, discloses a methodof preparing novel ferric organic compounds, including ferric citratethat has a large active surface area, and remains soluble over a widerrange of pH than previously described preparations. This publicationalso teaches using these novel ferric organic compounds in the treatmentof various disorders such as hyperphosphatemia and metabolic acidosis.Because they are more soluble, these novel forms of ferric organiccompounds can be used to more effectively deliver ferric organiccompounds by the route of oral administration to patients. However, thispublication did not provide any data to show whether these novel formsof ferric organic compounds would be useful in providing treatment forpatients with chronic kidney disease.

The present invention discloses these novel forms of ferric organiccompounds possess several characteristics beneficial for the treatmentor modification of chronic kidney disease.

SUMMARY OF THE INVENTION

In accordance with these and other objects of the invention, a briefsummary of the present invention is presented. Some simplifications andomission may be made in the following summary, which is intended tohighlight and introduce some aspects of the present invention, but notto limit its scope. Detailed descriptions of a preferred exemplaryembodiment adequate to allow those of ordinary skill in the art to makeand use the invention concepts will follow in later sections.

The present invention provides a method of treating a subject havingchronic kidney disease, comprising administering to said subject aneffective amount of a ferric organic compound that has a dissolutionrate of at least approximately 2 mg/cm²/min. An example of ferricorganic compound is ferric citrate. Representative ranges of thedissolution rate include, but are not limited to, from about 2.5mg/cm²/min to about 3.0 mg/cm²/min., or from about 3.0 mg/cm²/min toabout 3.5 mg/cm²/min., or from about 3.5 mg/cm²/min to about 4.0mg/cm²/min.

In one embodiment, the ferric organic compound is prepared according amethod comprising the steps of: (a) obtaining a ferric iron salt; (b)adding an alkaline metal hydroxide to the ferric iron salt underconditions effective to produce a mixture comprising polyiron oxide; (c)isolating a precipitate from the mixture; (d) adding an organic acid tothe precipitate; (e) forming a ferric organic acid solution by heatingthe organic acid and the precipitate; and (f) precipitating the ferricorganic compound from the ferric organic acid solution by adding anorganic solvent to the solution.

In general, a subject is a human or an animal. The subject may have anystage of chronic kidney disease (e.g. end stage renal disease), or isundergoing renal dialysis. The ferric organic compound may beadministered orally or any other appropriate route generally known inthe art and the ferric organic compound can be formulated into a numberof formats generally known in the art. Representative formats include,but are not limited to, a tablet, a powder, a suspension, an emulsion, acapsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit, ora syrup.

In one embodiment, treatment with the ferric organic compound results indecreased serum creatinine and BUN level in the subject. In anotherembodiment, treatment with the ferric organic compound results indecreased phosphorus and calcium and phosphorus product (CaxP) levels inserum.

In one embodiment, treatment with the ferric organic compound wouldprevent, reverse, maintain, or delay progression of chronic kidneydisease. In another embodiment, development of hyperparathyroidism, bonedisorder, or cardiovascular disease in the subject is prevented,reversed, maintained or delayed. In yet another embodiment, calciumphosphate precipitation in the subject's renal tissue is prevented,reversed, maintained or delayed. In yet another embodiment, kidney stoneformation is prevented, reversed, maintained or delayed. In still yetanother embodiment, development of metabolic acidosis in the subject isprevented, reversed, maintained or delayed.

The present invention also provides uses of a ferric organic compounddescribed herein for preparation of a medicament for treating a subjecthaving chronic kidney disease.

The present invention also provides a method of treating a subjecthaving chronic kidney disease, comprising administering to said subjectan effective amount of a ferric organic compound. An example of theferric organic compound is ferric citrate. In one embodiment, the ferricorganic compound has a dissolution rate of at least approximately 2mg/cm²/min.

The present invention also provides a therapeutic regimen for treating asubject having chronic kidney disease; the regiment comprises apharmaceutical composition comprising an acceptable carrier and aneffective amount of ferric organic compound having a dissolution rate ofat least 2 mg/cm²/min., wherein the pharmaceutical composition isadministered in single or multiple doses regimens.

The present invention also provides a pharmaceutical composition fortreating a subject having chronic kidney disease, the compositioncomprising an effective amount of a ferric organic compound having adissolution rate of at least approximately 2 mg/cm²/min.

The present invention also provides a use of the above pharmaceuticalcomposition in preparation of a medicament for treating a subject havingchronic kidney disease.

DETAILED DESCRIPTION OF THE FIGURES

In drawings which illustrate specific embodiments of the invention, butwhich should not be construed as restricting the spirit or scope of theinvention in any way:

FIG. 1 is a schematic diagram outlining the method of making novel formsof ferric organic compounds according to the present invention.

FIG. 2 is a comparison of the safety profiles of chemical grade andpharmaceutical grade ferric citrates

FIG. 3 is a comparison of the efficacy profiles of chemical grade andpharmaceutical grade ferric citrates

FIG. 4 shows a bar graph of the relationship between the rate ofdialysis patient mortality and hyperphosphatemia

FIG. 5 shows the serum creatinine levels of a patient (patient code:2-01-1-029) treated with 6 g/day of ferric citrate.

FIG. 6 shows the serum creatinine levels of a patient (patient code:2-01-1-032) treated with 6 g/day of ferric citrate.

DETAILED DESCRIPTION OF THE INVENTION

In drawings which illustrate specific embodiments of the invention, butwhich should not be construed as restricting the spirit or described indetail to avoid unnecessarily obscuring the invention. Accordingly, thespecification and drawings are to be regarded in an illustrative, ratherthan a restrictive, sense.

Results presented below indicate that treatment with ferric citrate, anexample of ferric organic compounds produced according to the methodsdescribed herein, would reduce serum concentrations of creatinine,phosphorus, calcium, and phosphorus product (CaxP) in patients withchronic kidney disease. Hence, ferric organic compounds of the presentinvention, including but not limited to ferric citrate, can be used tomodify the progression of chronic kidney disease (CKD) in a subject; forexample, the progression of CKD can be prevented, reversed, maintained,or delayed.

The present invention is not limited to using the ferric citratedisclosed herein. Other ferric citrate compounds, or their salts,derivatives, analogs, metabolites, or preparations that are suitable foruse in the methods of the present invention will be readily apparent toa person of ordinary skill in the art by following the teaching of thisapplication. Furthermore, methods of the present invention alsoencompass using other ferric organic compounds synthesized according tothe methods described herein. These ferric organic compounds preferablyhave or include the following properties:

high affinity for binding phosphorous;

soluble over a wide range of pH;

rapid binding independent of pH;

high solubility;

low absorption throughout the entire body;

lack of toxicity;

can be administered orally; and/or

inexpensive to produce.

In view of the data presented herein, one of ordinary skill in the artwould also readily realize that the present invention is not limited tousing ferric organic compounds produced according to the methoddisclosed herein. Hence, it will be readily apparent to a person ofordinary skill in the art that the present invention encompasses methodsof using ferric organic compounds to treat chronic kidney disease,wherein the ferric organic compounds possess certain characteristics asdescribed herein.

In one embodiment, the ferric organic compounds produced according tothe methods described herein are useful in the treatment ofhyperphosphatemia, metabolic acidosis, and any other disordersresponsive to ferric organic compound therapy. Because the ferricorganic compounds of the present invention are more soluble thancommercially available ferric organic compounds, smaller amounts of theferric organic compounds of the present invention can be used toeffectively treat patients suffering from such disorders.

In one embodiment of the invention, the ferric citrate of the presentinvention has a significantly higher rate of aqueous solubility underphysiological conditions than commercially available forms of ferriccitrate, and therefore the ferric citrate of the present invention isbelieved to provide a significant improvement in the orally effectiveuse of ferric citrate at a reduced dosage. By reducing the orallyeffective dose of ferric citrate, it is believed that the ferric citrateof the present invention will provide a lower incidence of ulcerativegastrointestinal adverse effects associated with commercially availableferric citrate compounds. In addition, it is believed that the increasedrate of dissolution of the ferric citrate of the present invention willprovide a more rapid onset of action in binding to dietary phosphate.Furthermore, the ferric organic compounds of the present invention aremore soluble over a wider pH range than commercially available ferricorganic compounds; therefore, the ferric organic compounds of thepresent invention can be more effective by being soluble in the smallintestine.

The ferric organic compounds of the present invention can beadministered in a number of forms generally known in the art.Pharmaceutical compositions comprising the ferric organic compounds ofthe present invention include, but are not limited to solids, liquids,or semi-solid forms, such as gels, syrups, chewables or pastes. Theferric organic compounds of the present invention can be administeredalone or in combination with a pharmaceutically acceptable carrier.Orally administrable forms include, but are not limited to, a tablet, apowder, a suspension, an emulsion, a capsule, a granule, a troche, apill, a liquid, a spirit, or a syrup. The composition can beadministered to human beings or other animals suffering from illnessesresponsive to ferric organic compound therapy.

An effective amount of pharmaceutical-grade ferric citrate can bereadily determined by one of ordinary skill in the art. For example, aneffective dose may be from 2 to 100 grams per day, preferably between 2and 60 grams per day. Alternatively, a daily effective amount may be 2,4, 6, or 8 grams.

Compositions comprising pharmaceutical grade ferric organic compounds ofthe present invention, such as ferric citrate, are suitable for treatinghyperphosphatemia, or other disorders characterized by high serumphosphate levels. Therefore, the invention encompasses treating subjectsor patients with various renal diseases; e.g., End Stage Renal Diseases(ESRD), Chronic Kidney Disease (CKD) or other relate kidney diseases, orsubjects and patients who are on dialysis but not limited tohemodialysis.

In one embodiment, compositions comprising pharmaceutical grade ferricorganic compounds of the present invention, such as ferric citrate, maybe used to treat subjects or patients with metabolic acidosis. Otherdisorders that may be ameliorated by the conversion of citrate tobicarbonate are also encompassed by the invention described.

In one embodiment, a method for using the pharmaceutical compositionencompasses treating a human or non-human subject or patient withchronic kidney disease. There are generally five clinical stages ofchronic kidney disease, numbered 1 to 5, wherein stage 1 is the leastsevere and stage 5 the most severe. In the early stages, e.g., stages 1and 2, dialysis is not required. As chronic kidney disease progresses tostage 5, a patient may require dialysis treatment three times per week.It should be noted that elevated phosphate levels are observed at allstages of chronic kidney disease. Therefore, an embodiment of theinvention is a method of treating a subject or person with early ormid-stage chronic kidney disease, with a composition comprisingpharmaceutical-grade ferric citrate in order to achieve a lower serumphosphate level.

In another embodiment, there is provided a method of treating a human ornon-human subject or patient with late-stage chronic kidney disease whois undergoing hemodialysis, by administering a composition comprisingpharmaceutical-grade ferric citrate of the present invention. It isgenerally known that hemodialysis is not sufficiently effective inreducing serum phosphate level. The treatment of a subject or personwith late stage kidney disease is applicable whether or not the subjector person is currently undergoing hemodialysis treatment.

An additional embodiment of the invention is a method of treating asubject or person with chronic kidney disease and undergoing peritonealdialysis with the pharmaceutical-grade ferric citrate-containingcompositions described herein. It is known that peritoneal dialysis isnot sufficiently effective in reducing serum phosphate levels.

The present invention provides a method of treating a subject havingchronic kidney disease. In general, the subject is a human or an animal.The subject may have end stage renal disease, or is undergoing renaldialysis. The method comprises the steps of administering to saidsubject an effective amount of a ferric organic compound that has adissolution rate of at least approximately 2 mg/cm²/min. Representativeranges of the dissolution rate include, but are not limited to, fromabout 2.5 mg/cm²/min to about 3.0 mg/cm²/min., or from about 3.0mg/cm²/min to about 3.5 mg/cm²/min., or from about 3.5 mg/cm²/min toabout 4.0 mg/cm²/min.

In one embodiment, the ferric organic compound is prepared according amethod comprising the steps of: (a) obtaining a ferric iron salt; (b)adding an alkaline metal hydroxide to the ferric iron salt underconditions effective to produce a mixture comprising polyiron oxide; (c)isolating a precipitate from the mixture; (d) adding an organic acid tothe precipitate; (e) forming a ferric organic acid solution by heatingthe organic acid and the precipitate; and (f) precipitating the ferricorganic compound from the ferric organic acid solution by adding anorganic solvent to the solution.

In one embodiment, the alkaline metal hydroxide is sodium hydroxide, theferric iron salt is ferric chloride hexahydrate, and the organic acid iscrystalline citric acid.

In general, the alkaline metal hydroxide (e.g. sodium hydroxide orpotassium hydroxide) is added at a rate of less than 20 ml/min,preferably between about 10 ml/min to about 20 ml/min., and the alkalinemetal hydroxide is added to the ferric iron salt at a temperature ofless than 40° C., preferably between about 10° C. to about 40° C. Theorganic acid and the precipitate are heated to a temperature of betweenabout 80° C. to about 90° C. Precipitating the ferric organic compoundfrom the ferric organic acid solution by an organic solvent comprisescooling the ferric organic acid solution to less than 30° C. beforeadding the organic solvent, preferably the ferric organic acid solutionis cooled to a temperature between about 10° C. to about 30° C.

A number of organic acids, such as citric acid, acetic acid, isocitricacid, succinic acid, fumaric acid, and tartaric acid can be used in themethod of synthesizing the ferric organic compound. In one embodiment,the organic acid is in crystalline form. Moreover, a number of organicsolvent, such as ethanol, methanol, butanol, isopropyl alcohol, acetone,and tetrahydrofuran can be used in synthesizing the ferric organiccompound described herein.

The ferric organic compound can be administered at an effective dosedetermined by one of ordinary skill in the art, for example 2-20 gm/day.The ferric organic compound can be administered orally or any otherappropriate route readily determined by one of ordinary skill in theart. In general, the ferric organic compound can be formulated as atablet, a powder, a suspension, an emulsion, a capsule, a lozenge, agranule, a troche, a pill, a liquid, a spirit, or a syrup.

In one embodiment, treatment with the ferric organic compound results indecreased serum creatinine and BUN level in the subject. In anotherembodiment, treatment with the ferric organic compound results indecreased phosphorus, calcium, and phosphorus product (CaxP) levels inserum.

In one embodiment, treatment with the ferric organic compound wouldprevent, reverse, maintain, or delay progression of chronic kidneydisease. In another embodiment, development of hyperparathyroidism, bonedisorder, or cardiovascular disease in the subject is prevented,reversed, maintained or delayed. In yet another embodiment, calciumphosphate precipitation in the subject's renal tissue is prevented,reversed, maintained or delayed. In yet another embodiment, kidney stoneformation is prevented, reversed, maintained or delayed. In still yetanother embodiment, development of metabolic acidosis in the subject isprevented, reversed, maintained or delayed.

The present invention also provides a method of treating a subjecthaving chronic kidney disease, comprising administering to said subjectan effective amount of a ferric organic compound, wherein the ferricorganic compound is prepared according a method comprising the steps of:(a) obtaining a ferric iron salt; (b) adding an alkaline metal hydroxideto the ferric iron salt under conditions effective to produce a mixturecomprising polyiron oxide; (c) isolating a precipitate from the mixture;(d) adding an organic acid to the precipitate; (e) forming a ferricorganic acid solution by heating the organic acid and the precipitate;and (f) precipitating the ferric organic compound from the ferricorganic acid solution by an organic solvent. This method of synthesishas been described herein to produce ferric organic compound (e.g.ferric citrate) that has enhanced dissolution rate (e.g. a dissolutionrate of at least about 2 mg/cm²/min.). This method of treatment wouldproduce therapeutic effects described above.

The present invention also provides a method of treating a subjecthaving chronic kidney disease, comprising administering to said subjectan effective amount of a ferric organic compound. Examples of ferricorganic compound include, but are not limited to, ferric citrate. Ingeneral, the subject is a human or an animal. The subject may have endstage renal disease, or is undergoing renal dialysis. In one embodiment,the ferric organic compound has a dissolution rate of at leastapproximately 2 mg/cm²/min.

The present invention also provides a therapeutic regimen for treating asubject having chronic kidney disease, the regiment comprises apharmaceutical composition comprising an acceptable carrier and aneffective amount of ferric organic compound having a dissolution rate ofat least 2 mg/cm²/min., wherein the pharmaceutical composition isadministered in single or multiple doses regimens. An example of ferricorganic compound is ferric citrate. As shown in Table 1, a ferricorganic compound such as ferric citrate having a dissolution rate of atleast 2 mg/cm²/min. would be useful in the present method. For example,the dissolution rate of the ferric organic compound can be fromapproximately 2.5 mg/cm²/min to approximately 3.0 mg/cm²/min., or fromapproximately 3.0 mg/cm²/min to approximately 3.5 mg/cm²/min., or fromapproximately 3.5 mg/cm²/min to approximately 4.0 mg/cm²/min. Ingeneral, at least a portion of the pharmaceutical composition isadministered orally. In one embodiment, the subject is having end stagerenal disease, and the method may optionally comprise renal dialysis orperitoneal dialysis.

The present invention also provides a pharmaceutical composition fortreating a subject having chronic kidney disease, the compositioncomprising an effective amount of a ferric organic compound (e.g. ferriccitrate) having a dissolution rate of at least approximately 2mg/cm²/min. In one embodiment, the dissolution rate is from about 2mg/cm²/min to about 4 mg/cm²/min. In general, the composition is in aform suitable for oral administration, e.g. as a tablet, a powder, asuspension, an emulsion, a capsule, a lozenge, a granule, a troche, apill, a liquid, a spirit, or a syrup.

The present invention also provides a use of the above pharmaceuticalcomposition in preparation of a medicament for treating a subject havingchronic kidney disease. In one embodiment, the subject is having endstage renal disease or undergoing renal dialysis.

The following examples are intended to illustrate embodiments of theinvention but which are not intended to limit the scope of theinvention.

Example 1 General Method for Synthesis of a Pharmaceutical-Grade FerricOrganic Compound

General methods for the synthesis of ferric organic compounds have beendisclosed in PCT/US2006/032585, and U.S. provisional application No.60/763,253, which are incorporated by reference into this application.Representative ferric organic compounds include, but are not limited to,ferric citrate.

Referring to FIG. 1, the flowchart 10 is a general process forsynthesizing a form of ferric organic compound or ferric citratecompound which can be used in the present invention. The startingmaterials, as indicated in box 20, comprise soluble ferric iron salts.The soluble ferric iron salts can comprise ferric chloride hexahydrate(FeCl₃6H₂O), as indicated in box 21, or any other suitable solubleferric iron salt. Next, an alkaline metal hydroxide (box 30) is added ata specific rate and temperature to the soluble ferric iron salt. Theaddition of the alkaline metal hydroxide at a specific rate, preferablybetween about 10 ml/min and about 20 ml/min, and temperature range,preferably below 40° C., results in the formation of a uniform polyironoxo colloidal suspension. The alkaline metal hydroxide can comprisesodium hydroxide, potassium hydroxide, or any other suitable alkalinemetal hydroxide as indicated in box 31.

The colloidal suspension precipitate is collected and rinsed (box 40)with distilled water to remove any soluble impurities. After rinsing,the precipitate is re-suspended and, as indicated in box 50, crystallineorganic acid is added to the precipitate and heated to a particulartemperature range, preferably between about 80° C. to about 90° C. Theorganic acid can comprise any suitable organic acid. Box 51 lists someof the possible organic acids which can be used, including, but notlimited to, citric acid, acetic acid, isocitric acid, succinic acid,fumaric acid, and tartaric acid. The addition of the organic acid allowsthe acid to form complexes with the precipitate in solution. At box 60,the ferric organic compound is precipitated out of solution with anorganic solvent to form a novel form of ferric organic compound (box70). Various organic solvents can be used, including, but not limitedto, the solvents described in box 61, such as ethanol, methanol,butanol, acetone, isopropyl alcohol, tetrahydrofuran, or any othersuitable organic solvent.

Synthesis of Ferric Citrate

In one embodiment of the invention, the ferric organic compound isferric citrate. The starting materials for making a ferric citratecomprise a 1.85M solution of ferric chloride hexahydrate (FeCl₃6H₂O). Avolume of 5M sodium hydroxide necessary to produce a 1:3 ratio of ferriciron to hydroxide ion is added to the ferric chloride hexahydratesolution at a rate of less than 20 ml per minute, preferably betweenabout 10 ml per minute and about 20 ml per minute. The temperature ofthe mixture is maintained below 40° C., preferably between about 10° C.to about 40° C., while the sodium hydroxide is added to form a polyironoxide colloidal suspension of ferric hydroxide. The pH of the suspensionis measured while the sodium hydroxide is added. Once the pH is above7.0, the suspension is cooled until it is less than 30° C., preferablybetween about 10° C. to about 30° C. The suspension is then filteredthrough a 1 mm pore filter to breakup aggregates and large particles offerric hydroxide precipitate are then removed. The filtered ferrichydroxide suspension is then centrifuged. The supernatant is discarded,and the precipitated ferric hydroxide is centrifuged again to remove anyremaining supernatant. The ferric hydroxide precipitate is thenresuspended with distilled water. The centrifugation-resuspension stepsare repeated two more times to wash the ferric hydroxide precipitate andremove water soluble impurities. The resulting ferric hydroxideprecipitate is then homogenized.

An amount of citric acid necessary to produce a 1:1 ratio of ferric ironto citrate is added to the precipitate. The mixture is heated to betweenabout 80° C. to about 90° C. in an oil bath until the color of themixture changes from orange-brown to a clear black-brown, or until allof the ferric hydroxide precipitate is dissolved. The reaction is cooleduntil it is less than 30° C., preferably between about 10° C. to about30° C., and the pH is measured to determine that it is within 0.8 and1.5. The reaction is centrifuged, and the supernatant is collected.Ferric citrate is precipitated from the supernatant by adding 5 volumesof organic solvent.

Various organic solvents can be used, including ethanol, methanol,butanol, acetone, isopropyl alcohol, or tetrahydrofuran. Once thesolvent is added, the mixture is stirred until a light beige precipitateforms. The suspension is centrifuged and the supernatant is discarded.The precipitate is washed and centrifuged with the solvent two moretimes. The precipitate is then dried in a vacuum oven for 8 to 16 hoursat ambient temperature or by any other suitable industrial processessuch as fluidized-bed drying. The dried precipitate is ground with amortar and pestle and dried for another 8 to 24 hours at ambienttemperature. The fine precipitate is finely ground by milling again andscreened through a 45 mesh size (35 micron) sieve. The novel form offerric citrate powder is dried in the vacuum oven again or fluidized-beddrying again and dried at ambient temperature until 1 hour of dryingleads to less than 0.25% loss in weight.

Example 2 Solubility Profile of Ferric Organic Compounds According tothe Invention

The ferric organic compounds produced according to the methods describedabove are more soluble than commercially available ferric organiccompounds, over a wider range of pH levels. This increase in solubilityof the ferric organic compounds of the present invention is believed tobe a result of the unique significantly large active surface area of theferric organic compounds of the present invention. For example, at pH8.0, the intrinsic dissolution rate of ferric citrate of the presentinvention is 3.32 times greater than the commercially available ferriccitrate. See Table 1.

The intrinsic dissolution rates of commercially available ferric citratewere compared with the ferric citrate of the present invention. Theintrinsic dissolution rate is defined as the dissolution rate of puresubstances under the condition of constant surface area. The dissolutionrate and bioavailability of a drug substance is influence by its solidstate properties: crystallinity, amorphism, polymorphism, hydration,solvation, particle size and particle surface area. The measuredintrinsic dissolution rate is dependent on these solid-state propertiesand is typically determined by exposing a constant surface area of amaterial to an appropriate dissolution medium while maintaining constanttemperature, stirring rate, and pH. The intrinsic dissolution rates arepresented in Table 1.

TABLE 1 Intrinsic Dissolution Rates of Ferric Citrate at 37° C. inSolutions of pH 8 Rate of Intrinsic Mean Intrinsic Acetone DissolutionDissolution Addition Rates Rates Sample (ml/min) (mg/cm2/min)(mg/cm2/min) RFS-12 (sigma/ 10.0 0.83 0.83 commercially available)STM-134 10.0 1.88 1.88 (reference material) PAN031203A 10.0 3.82 3.32(experimental batch 1) PAN031203B 10.0 4.00 (experimental batch 2)PAN031203C 9.5 2.68 (experimental batch 3) PAN031203D 40 2.95(experimental batch 4) PAN031203E 4.4 3.13 (experimental batch 5)

The BET active surface area of the ferric citrate of the presentinvention is at least 16 times larger than the commercially availableferric citrate. See Table 2.

The analysis of active surface area is based on BET theory whichdescribes the phenomenon of mass and energy interaction and phasechanges during gas adsorption onto solid surfaces and in pore spaces. InBET active surface area measurement, the volume of a monolayer of gas isdetermined which allows the surface area of the sample to be determinedusing the area occupied by a single layer of adsorbed gas molecule.Table 2 is a comparison of the active surface area of the ferric citrateof the present invention compared to the active surface area ofcommercially available ferric citrate compounds.

TABLE 2 BET Active Surface Areas of Various Forms of Ferric Citrate MeanBET Dissolution Active Rates Surface Sample (mg/cm2/min) Area RFS-12-1(sigma/commercially 0.76 0.61 available) RFS-12-2 (sigma/commerciallyavailable) STM-134-1 (reference material 1) 2.47 16.17 STM-134-2(reference material 2) STM-182-1 (lab-scale 500 g batch 1) 2.61 19.85STM-182-2 (lab-scale 500 g batch 2)

Example 3 Methods of Using and Testing the Pharmaceutical-Grade FerricCitrate in Patients Handling and Forms of Test Compositions

Ferric citrate is supplied in 500 mg capsules, whereas the placebo willbe provided in identical-looking capsules (indistinguishable from thosecontaining the active drug); the placebo capsules will contain sorbitoland colorant to match the powder color of the active capsules. Theplacebo capsule shells will be identical to the active capsule shells.

Storage

All study drug supplies must be stored under secure conditions and arenot to be used after their expiration date, which is imprinted on thestudy drug container. The study drugs should be kept under controlledconditions (15 to 30° C.; 59 to 86° F.) in a tightly closed container,protected from light.

Dosage

A recent pilot study compared ferric citrate (3 g daily) to calciumcarbonate (3 g daily) for reducing serum PO₄ in patients with End StageRenal Disease (ESRD). This dose of ferric citrate was associated withmild, but tolerable GI symptoms.

The doses of ferric citrate chosen for study or treatment may be from 1to 30 grams of ferric citrate per day. In part, this may depend on thenature of the formulation provided. For example, ferric citrate capsulesmay be administered up to a daily dose of about 15 grams/day, whereasthe tablet form may be administered up to 30 grams/day. Thus, there is avery broad range of dosing regimens encompassed by the invention.

Titration of Optimal Dosage for a Subject

In the context of this invention, the term “subject” refers to either ahuman or non-human animal. The optimal dosage of an individual subjector groups may be determined as follows. A dose of approximately one ortwo grams per day is merely suggested as an illustrative starting dose.The daily dose may be increased as needed until the desired result isobserved.

The intent of the invention is to not limit the dose range employed.Therefore, depending on the subject(s) the daily dose administered mayapproximate thirty, forty, fifty, sixty, seventy, eighty, ninety or onehundred grams per day. The safety profile of the pharmaceutical-gradeferric citrate allows the implementation of a broad range of doses.

Further, is the intent of the invention to not be limited to capsulesand tablets as oral formulations. It is known in the art that a widevariety of oral formulations may be adapted for use with the invention.

Illustrative Example of a Dosage Regimen

An non-limiting example of a dosing regimen is provided below. This isnot meant to limit the invention as to how an effective amount of ferriccitrate is selected, or the form in which it is provided or thefrequency of administering the composition per day. The following merelyillustrates how ferric citrate and placebo may be administered; e.g., as500 mg capsules of identical appearance. All patients may receive (in ablinded fashion) 4 capsules with each of three meals, on a daily basis,for 28 days. Patients will be instructed to take the study medicationwithin 10 minutes of finishing their meals (breakfast, lunch, anddinner).

The number of placebo, and active capsules to be taken at each meal, areas follows:

Placebo Arm of the Study

4 placebo capsules, with breakfast

4 placebo capsules, with lunch

4 placebo capsules with dinner

Ferric citrate 2 g per day arm of the study

1 ferric citrate capsule and 3 placebo capsules with breakfast

1 ferric citrate capsule and 3 placebo capsules with lunch

2 ferric citrate capsules and 2 placebo capsules with dinner

Ferric citrate 4 g per day arm

2 ferric citrate capsules and 2 placebo capsules with breakfast

3 ferric citrate capsule and 1 placebo capsule with lunch

3 ferric citrate capsules and 1 placebo capsule with dinner

Ferric citrate 6 g per day arm

4 ferric citrate capsules with breakfast

4 ferric citrate capsules with lunch

4 ferric citrate capsules with dinner

Clinical Schedule and Assessments

Each patient's participation in the trial lasts for up to 8 weeks: thescreening period (approximately 1-2 weeks), a 1-2 week washout, and 4weeks of treatment with study medication.

Screening Visit 1 (Study Days—30 to-15)

The following procedures will be performed at the first screening visit:

1. Medical history, including concomitant medications.

2. Demographic data.

3. Physical examination, including height, weight, and vital signs.

4. Dietary interview, using 24 hour recall method, to assess dietaryintake of calcium and phosphorous, three times during screening period,to include one dialysis day, one non-dialysis day, and one weekend day.Note: Dietary interview may be also performed, in part or in whole,during the washout period.

5. Laboratory assessment:

a. Hematology: complete blood count (CBC) with differential, platelets.

b. Chemistries: sodium, potassium, chloride, bicarbonate, blood ureanitrogen (BUN), creatinine, glucose (random), aspartate transaminase(AST), alanine transaminase (ALT), alkaline phosphatase (ALP), totalbilirubin, total protein, albumin, serum calcium, serum phosphate,magnesium

c. Total and LDL cholesterol levels

d. Serum (3-HCG for women of childbearing potential

e. Iron panel: serum iron, ferritin, transferrin saturation percentage,and total iron binding capacity.

6. 12-lead ECG.

7. Patients will be given instructions for the Washout Period (StudyDays—14 to-1):

a. All phosphate-binding agents will be discontinued at Day—14

b. Any iron therapy (oral or intravenous) will be discontinued at Day—14

c. Patients who have been receiving a stable dose of vitamin D orcalcitriol for I month prior to enrollment will be instructed tomaintain their current dose throughout the study

d. Patients will be advised to avoid changes in diet, calcium ormagnesium containing antacids (other medications).

Screening Visit 2 (Study Days—7+/−1 Day)

Laboratory Assessment of serum PO₄. Patients with a Day—7 serum PO₄≥5.5mg/dL and ≤10 mg/dL may be randomized before the 2-week washout iscomplete. The day of randomization will automatically become Day 0.Patients with a Day—7 phosphate level of ≤10 mg/dL will be removed fromthe study and instructed to resume their pre-study medications.

Study Day 0 (Randomization and Dosing)

1. Physical examination, including weight and vital signs.

2. Adverse event query.

3. Concomitant medication query.

4. Baseline Laboratory assessments:

a. Serum P04;

b. Serum Ca;

c. Iron panel: serum iron, ferritin, transferrin saturation percentage,and total iron binding capacity. The Baseline Laboratory Assessments maybe done up to 3 days prior to Day 0.

5. Patients with a P0₄ level≥0.5 mg/dL and ≤10 mg/dL will be randomizedand a 15-day supply of study medication will be dispensed. Patientsshould be instructed to begin taking study medication within 10 minutesof completing their next meal on Day 0.

Study Day 14 (Midpoint Evaluation)

The following procedures will be performed at Study Day 14+/−1 day.

1. Physical examination including weight and vital signs.

2. Adverse event query.

3. Concomitant medication query.

4. Dispense an additional 15-day supply of study medication. Allreturned capsules should be counted and recorded in the Case ReportForm.

5. Laboratory assessment:

a. Hematology: CBC with differential, platelets.

b. Chemistries: sodium, potassium, chloride, bicarbonate, BUN,creatinine, glucose (random), AST, ALT, ALP, total bilirubin, totalprotein, albumin, calcium, phosphate, magnesium.

c. Iron panel: serum iron, ferritin, transferrin saturation percentage,and total iron binding capacity.

d. Total and LDL cholesterol levels.

Note: Patients with a Day 14 phosphate level of >10 mg/dL will beremoved from the study and instructed to resume their pre-studymedications.

Study Day 28 (End of Study Evaluation)

The following procedures will be performed at Study Day 28+/−1 day or onthe day of early termination.

1. Physical examination including weight and vital signs

2. Adverse event query.

3. Concomitant medication query.

4. Laboratory assessment:

a. Hematology: CBC with differential, platelets

b. Chemistries: sodium, potassium, chloride, bicarbonate, BUN,creatinine, glucose (random), AST, ALT, ALP, total bilirubin, totalprotein, albumin, calcium, phosphate, magnesium.

c. Total and LDL cholesterol levels

d. Iron panel: serum iron, ferritin, transferrin saturation percentage,and total iron binding capacity.

5. 12-lead ECG

6. Patients will be instructed to resume their pre-study medicationsafter completing the study.

Data Management and Analysis

GloboMax will be the primary data management, monitoring, andcoordinating center. Case report forms (CRF) will be provided for eachsubject. Subjects will not be identified by name or initials on CRFs.The CRF will be monitored at the clinical sites and collected byGloboMax's study monitor. Audited CRFs will be used to create electronicdata files.

Three major categories of endpoints reflect biochemical and clinicalissues being addressed at the outset. Additional clinical andbiochemical issues are addressed as they arise. Therefore, the endpointsare not meant to limit the totality of relevant findings andmeasurements collected in these, or future studies.

Primary Endpoints

The change in serum PO₄ concentration at Days 14 and 28 from baseline.

Secondary Endpoints

The change in serum calcium concentration at Days 14 and 28 frombaseline.

The change in iron, ferritin, transferrin saturation percentage, andtotal iron binding capacity at Days 14 and 28 from baseline.

The change in the Ca′PO₄ product at Days 14 and 28 from baseline.

Safety Endpoints

Safety will be monitored by recording adverse events and the results ofphysical examinations, vital signs and laboratory tests at each studyvisit.

Specific rules for withdrawal from the study, based on laboratory data,have also been set up to ensure patient safety. A nonlimiting example ofsuch criteria is illustrated by the following:

If a patient's serum phosphate level increases to ≥10 mg/dL at any timeduring the study period, the patient will be withdrawn from the study.

Example 4 Randomized, Double-Blind, Placebo-Controlled, Dose-RangingStudy of the Effects of Ferric Citrate on Serum Phosphate in Patientswith End Stage Renal Disease (ESRD)

Objectives: (1) To determine the effect of ferric citrate at doses of 2,4 and 6 g daily, administered TID (three times a day), for 28 days onserum phosphate (PO4) levels in patients with end stage renal disease(ESRD). (2) To evaluate the safety of ferric citrate at doses of 2, 4, 6g daily, administered TID, for 28 days in patients with ESRD.

Study Drug: Ferric citrate disclosed in U.S. Ser. No. 11/206,981 and WO2004/07444.

Study Design: Randomized, double-blind, placebo-controlled, dose-rangingstudy to assess the effect of ferric citrate on serum phosphateconcentrations in patients with ESRD on hemodialysis. Patients areassessed at Study Days 14 and 28 for effectiveness as measured by serumphosphate concentrations. Patients who received one or more doses ofstudy medication are also assessed for safety.

Study Duration: 8 weeks (including the screening period, 2 weekswashout, 4 weeks treatment)

Results show a decrease in serum PO4 and Ca*PO4 at 0, 2, and 6 gm/day(given as TID immediately after meals, i.e., within 10 minutes). Ferriccitrate is administered orally, and is given equally three times a day.

The ability of ferric citrate to lower the serum phosphate levels inpatients with ESRD was demonstrated. No significant change was observedin the serum calcium level during the 28 days for placebo, 2, 4, and 6gm/day. However, the Ca*PO4 levels have decreased and were statisticallysignificant for 6 gm/day dose at both 14 and 28 days. The results alsoindicate that calcification may be reversed or stabilized followingtreatment with ferric citrate. The Tables below summarize the data thestudy.

TABLE 3 Summary of Results Dose Response Statistical Significant LinearRegression Serum PO4 (mg/dL) Day 14 No No P = 0.0523 Day 28 Yes Yes (6g/day) P = 0.0073 Serum Ca (mg/dL) Day 14 No No N.S. Day 28 No No N.S.Ca × PO4 (mg/dL)² Day 14 Yes No P = 0.0401 Day 28 Yes Yes (6 g/day) P =0.0158 * N.S.: Not Significant

TABLE 4 Summary of Serum [PO4] (mg/dL) Placebo 2 g/day 4 g/day 6 g/dayDose (N = 16) (N = 31) (N = 32) (N = 32) Response Serum [PO4] (mg/dL) atDay 0 7.2 ± 1.43 7.2 ± 1.23 7.1 ± 1.27 7.3 ± 1.33 N/A Serum [PO4](mg/dL) at Day 14 6.7 ± 1.22 6.7 ± 1.50 6.4 ± 1.56 6.3 ± 1.72 No (P =0.0523) Serum [PO4] (mg/dL) at Day 28 7.2 ± 1.19 6.9 ± 2.22 6.0 ± 1.33 5.8 ± 1.76* Yes *P < 0.05, Significant Difference Baseline Change asCompared to Placebo

TABLE 5 Summary of Serum [Ca] (mg/dL) Placebo 2 g/day 4 g/day 6 g/dayDose (N = 16) (N = 31) (N = 32) (N = 32) Response Serum [Ca] (mg/dL) atDay 0 8.71 ± 0.779 8.78 ± 0.981 9.02 ± 0.913 8.99 ± 0.812 No Serum [Ca](mg/dL) at Day 14 8.91 ± 0.782 9.01 ± 1.232 9.47 ± 0.990 9.13 ± 0.909 NoSerum [Ca] (mg/dL) at Day 28 8.74 ± 0.830 9.00 ± 0.953 9.29 ± 0.960 9.26± 0.865 No *P < 0.05, Significant Difference Baseline Change as Comparedto Placebo

TABLE 6 Summary of Serum [Ca]*[PO4] (mg/dL)² Placebo 2 g/day 4 g/day 6g/day Dose (N = 16) (N = 31) (N = 32) (N = 32) Response [Ca]*[PO4](mg/dL)² at Day 0 62.8 ± 13.91 62.9 ± 13.25 63.5 ± 10.69 65.8 ± 12.19N/A [Ca]*[PO4] (mg/dL)² at Day 14 59.9 ± 12.19 60.3 ± 16.50 59.9 ± 13.8957.5 ± 16.27 Yes [Ca]*[PO4] (mg/dL)² at Day 28 63.2 ± 12.55 61.7 ± 21.2555.4 ± 13.36  54.1 ± 17.68* Yes *P < 0.05, Significant DifferenceBaseline Change as Compared to Placebo

TABLE 7 Treatment-Emergent Adverse Events Placebo 2 g/day 4 g/day 6g/day (N = 16) (N = 33) (N = 34) (N = 33) # Event (%) # Event (%) #Event (%) # Event (%) Total number of subjects with at 7 (43.8) 16(48.5) 12 (35.3) 17 (51.5) least one adverse event (T#at1AE) Sorted byPreferred Term (PT) Abdominal Pain 0 (0.0) 0 (0.0) 4 (11.8) 2 (6.1)Diarrhea 2 (12.5) 3 (9.1) 1 (2.9) 1 (3.0) Sorted by System OrganClass/PT GI Disorders (see above PT) 4 (25.0) 8 (24.2) 10 (29.4) 10(30.3) General Disorders 2 (12.5) 4 (12.1) 2 (5.9) 4 (12.1) Infectionsand Infestations 2 (12.5) 0 (0.0) 3 (8.8) 1 (3.0) Skin and SC TissueDisorders 0 (0,0) 3 (9.1) 0 (0.0) 4 (12.1) Sorted by SOC/PT/SeverityT#at1AE, Mild 7 (43.8) 13 (39.4) 9 (26.5) 14 (42.4) T#at1AE, Moderate 0(0.0) 6 (18.2) 3 (8.8) 2 (6.1) T#at1AE, Severe 1 (6.3) 0 (0.0) 2 (5.9) 1(3.0) GI Disorders, Mild 4 (25.0) 6 (18.2) 8 (23.5) 9 (27.3) Sorted bySOC/PT/Relationship T#at1AE, Definitely 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)T#at1AE, Probably 1 (6.3) 2 (6.1) 2 (5.9) 5 (15.2) T#at1AE, Possibly 3(18.8) 5 (15.2) 6 (17.6) 2 (6.1) GI Disorder, Definitely 0 (0.0) 0 (0.0)0 (0.0) 0 (0.0) GI Disorder, Probably 1 (6.3) 2 (6.1) 2 (5.9) 5 (15.2)GI Disorder, Possibly 3 (18.8) 3 (9.1) 6 (17.6) 1 (3.0)

As shown in FIGS. 2 and 3, treatments using pharmaceutical-grade ferriccitrate provide several advantages over chemical grade ferric citrate.In general, while pharmaceutical-grade ferric citrate demonstrates anefficacy approximately equal to that of chemical grade ferric citrate,it achieves this result with less adverse side effects than chemicalgrade ferric citrate.

FIG. 2 also indicates that adverse side effects associated withadministering pharmaceutical-grade ferric citrate were not statisticallydifferent from those associated with the placebo. An advantage of thissafety profile is that an individual patient may have his dosing ofpharmaceutical-grade ferric citrate titrated over a broad range of doseswith less concern about side effect. In this way, a patient's individualtreatment may be tailored to suit his specific needs and tolerances.

Decrease in Serum Creatinine Level

Glomerular filtration rate (GFR) level correlates with structural kidneydamage and is used as a golden standard to measure kidney function. GFRcan be estimated by the biomarkers serum creatinine. As renal functiondeteriorates, kidney lost its function to excrete creatinine effectivelyand lead to creatinine retention in the body. Therefore, increase ofserum creatinine indicates lowering GFR and is an important sign ofkidney deterioration.

In an open-label extension of a Phase II clinical study: “randomized,double-blind, placebo-controlled, dose-ranging study of the effects offerric citrate on serum phosphate in patients with end stage renaldisease (ESRD)”, some of the patients were administered 2-6 g/day offerric citrate and serum creatinine level was monitored to assess kidneyfunction. Several patients who received 6 g/day of ferric citrate appearto have a trend of decreased serum creatinine level, which impliesferric citrate may modify, delay, and arrest or prevent the progressionchronic kidney disease. Results from 2 patients are shown in FIGS. 5-6.

What is claimed is:
 1. A method of treating a subject having chronickidney disease, comprising administering to said subject an effectiveamount of a ferric organic compound having a dissolution rate of atleast approximately 2 mg/cm²/min.
 2. The method of claim 1, wherein thedissolution rate of the ferric organic compound is from approximately2.5 mg/cm²/min to approximately 3.0 mg/cm²/min.
 3. The method of claim1, wherein the dissolution rate of the ferric organic compound is fromapproximately 3.0 mg/cm²/min to approximately 3.5 mg/cm²/min.
 4. Themethod of claim 1, wherein the dissolution rate of the ferric organiccompound is from approximately 3.5 mg/cm²/min to approximately 4.0mg/cm²/min.
 5. The method of any one of claims 1-4, wherein the ferricorganic compound is prepared according a method comprising the steps of:a) obtaining a ferric iron salt; b) adding an alkaline metal hydroxideto the ferric iron salt under conditions suitable to produce a mixturecomprising polyiron oxide; c) isolating a precipitate from the mixture;d) adding an organic acid to the precipitate; e) heating the organicacid and the precipitate, thereby forming a ferric organic acidsolution; and f) precipitating a ferric organic compound from the ferricorganic acid solution by an organic solvent.
 6. The method of claim 5,wherein the alkaline metal hydroxide is sodium hydroxide or potassiumhydroxide.
 7. The method of claim 5 or 6, wherein the alkaline metalhydroxide is added at a rate of less than 20 ml/min., and the alkalinemetal hydroxide is added to the ferric iron salt at a temperature ofless than 40° C.
 8. The method of any one of claims 5-7, wherein theorganic acid and the precipitate are heated to a temperature of betweenabout 80° C. to about 90° C., and precipitating the ferric organiccompound from the ferric organic acid solution by an organic solventcomprises cooling the ferric organic acid solution to less than 30° C.before adding the organic solvent.
 9. The method of any one of claims5-8, wherein the organic acid is in crystalline form.
 10. The method ofany one of claims 5-9, wherein the organic acid is selected from thegroup consisting of citric acid, acetic acid, isocitric acid, succinicacid, fumaric acid, and tartaric acid.
 11. The method of any one ofclaims 5-10, wherein the organic solvent is selected from the groupconsisting of ethanol, methanol, butanol, isopropyl alcohol, acetone,and tetrahydrofuran.
 12. The method of any one of claims 5-11, whereinthe ferric iron salt is ferric chloride hexahydrate, the alkaline metalhydroxide is sodium hydroxide, and the organic acid is crystallinecitric acid.
 13. The method of any one of claims 1-12, wherein thesubject is a human or an animal.
 14. The method of any one of claims1-13, wherein the chronic kidney disease includes any stage of chronickidney disease and end stage renal disease
 15. The method of any one ofclaims 1-14, wherein the subject is undergoing renal dialysis.
 16. Themethod of any one of claims 1-15, wherein the ferric organic compound isadministered at a dose of about 2-20 gm/day
 17. The method of any one ofclaims 1-16, wherein the ferric organic compound is administered orallyor any other appropriate route.
 18. The method of any one of claims1-17, wherein the ferric organic compound is formulated as a tablet, apowder, a suspension, an emulsion, a capsule, a lozenge, a granule, atroche, a pill, a liquid, a spirit, or a syrup.
 19. The method of anyone of claims 1-18, wherein treatment with the ferric organic compoundresults in decreased serum level of one or more substances in thesubject, said substances are selected from the group consisting ofcreatinine, BUN, phosphorus, and calcium and phosphorus product (CaxP).20. The method of any one of claims 1-18, wherein treatment with theferric organic compound results in preventing, reversing, maintaining ordelaying one or more conditions in the subject, said conditions areselected from the group consisting of progression of chronic kidneydisease, development of hyperparathyroidism, development of bonedisorder, development of cardiovascular disease, calcium phosphateprecipitation in renal tissue, kidney stone formation, and developmentof metabolic acidosis.
 21. A method of treating a subject having chronickidney disease, comprising administering to said subject an effectiveamount of a ferric organic compound.
 22. The method of claim 21, whereinthe ferric organic compound is administered orally.
 23. The method ofclaim 21, wherein the subject is a human or an animal.
 24. The method ofclaim 21, wherein the subject is having any stage of chronic kidneydisease, or is undergoing renal dialysis.
 25. The method of claim 21,wherein the ferric organic compound is formulated as a tablet, a powder,a suspension, an emulsion, a capsule, a lozenge, a granule, a troche, apill, a liquid, a spirit, or a syrup.
 26. The method of claim 21,wherein the ferric organic compound has a dissolution rate of at leastapproximately 2 mg/cm²/min.
 27. The method of any one of claims 21-26,wherein treatment with the ferric organic compound results in decreasedserum level of one or more substances in the subject, said substancesare selected from the group consisting of creatinine, BUN, phosphorus,calcium and phosphorus product (CaxP).
 28. The method of any one ofclaims 21-26, wherein treatment with the ferric organic compound resultsin preventing, reversing, maintaining or delaying one or more conditionsin the subject, said conditions are selected from the group consistingof progression of chronic kidney disease, development ofhyperparathyroidism, development of bone disorder, development ofcardiovascular disease, calcium phosphate precipitation in renal tissue,kidney stone formation, and development of metabolic acidosis.
 29. Themethod according to any one of claims 21-28, wherein the ferric organiccompound is ferric citrate.
 30. A therapeutic regimen for a subjecthaving chronic kidney, the regiment comprising a pharmaceuticalcomposition comprising an acceptable carrier and an effective amount offerric organic compound having a dissolution rate of at least 2mg/cm²/min., wherein the pharmaceutical composition is administered insingle or multiple doses regimens.
 31. The therapeutic regimen of claim30, wherein the dissolution rate of the ferric organic compound is fromapproximately 2.5 mg/cm²/min to approximately 3.0 mg/cm²/min.
 32. Thetherapeutic regimen of claim 30, wherein the dissolution rate of theferric organic compound is from approximately 3.0 mg/cm²/min toapproximately 3.5 mg/cm²/min.
 33. The therapeutic regimen of claim 30,wherein the dissolution rate of the ferric organic compound is fromapproximately 3.5 mg/cm²/min to approximately 4.0 mg/cm²/min.
 34. Thetherapeutic regimen of any one of claims 30-33, wherein at least aportion of the pharmaceutical composition is administered orally. 35.The therapeutic regimen of claim 30, wherein the chronic kidney diseaseincludes any stage of chronic kidney disease and end stage renaldisease.
 36. The therapeutic regimen of any one of claims 30-35, furthercomprising renal dialysis or peritoneal dialysis.
 37. The therapeuticregimen of any one of claims 30-36, wherein the ferric organic compoundis formulated as a tablet, a powder, a suspension, an emulsion, acapsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit, ora syrup.
 38. The therapeutic regimen according to any one of claims30-37, wherein the ferric organic compound is ferric citrate.
 39. Apharmaceutical composition for treating a subject having chronic kidneydisease, the composition comprising an effective amount of a ferricorganic compound having a dissolution rate of at least approximately 2mg/cm²/min.
 40. The pharmaceutical composition of claim 39, wherein thedissolution rate of the ferric organic compound is from about 2mg/cm²/min to about 4 mg/cm²/min.
 41. The pharmaceutical composition ofclaim 39 or 40, wherein the ferric organic compound is ferric citrate.42. The pharmaceutical composition of any one of claims 39-41, whereinthe composition is in a form suitable for oral administration.
 43. Thepharmaceutical composition of claim 42, wherein the form suitable fororal administration is a tablet, a powder, a suspension, an emulsion, acapsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit, ora syrup.
 44. A use of the pharmaceutical composition of any one ofclaims 39-43 in preparation of a medicament for treating a subjecthaving chronic kidney disease.
 45. The use of claim 44, wherein thesubject is having any stage of chronic kidney disease, or is undergoingrenal dialysis.